CN113912510B - 一种甲氧氯普胺双氯新杂质和用途 - Google Patents
一种甲氧氯普胺双氯新杂质和用途 Download PDFInfo
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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Abstract
本发明首次公开了一种甲氧氯普胺双氯新杂质，且制备得到的甲氧氯普胺双氯新杂质纯度大于99%，可以作为对照品用于甲氧氯普胺的质量研究，该杂质在甲氧氯普胺或其盐的原料药、制剂有关物质检测时作为杂质对照品，实现了对甲氧氯普胺更为严格的质量控制。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及一种甲氧氯普胺双氯新杂质和用途。
背景技术
甲氧氯普胺，又名氯普胺，英文名为metoclopramide，分子式是C14H22ClN3O2，分子量为299.7964，CAS登记号为364-62-5，白色至淡黄色结晶性粉末，有强大的中枢性镇吐作用。
甲氧氯普胺可用于因脑部肿瘤手术、肿瘤的放疗及化疗、脑外伤后遗症、急性颅脑损伤以及药物所引起的呕吐。对于胃胀气性消化不良、食欲不振、嗳气、恶心、呕吐也有较好的疗效，也可用于海空作业引起的呕吐及晕车(船)。除此之外，甲氧氯普胺亦可减轻钡餐检查时的恶心、呕吐反应，促进钡剂通过；或十二指肠插管前服用，有助于顺利插管；或用于胆道疾病和慢性胰腺炎的辅助治疗。
申请人采用的甲氧氯普胺原料药合成路线如下：
在合成过程中发现有未知的杂质，通过对IM2物料的结晶和母液分离富集，得到一个全新的杂质，如式I所示。
在新药研发过程中，药物的杂质含量将直接影响到药物的疗效和毒副作用，因此控制杂质限度、提高纯度对于保证药物的安全性、有效性和质量可控性至关重要。故本发明对甲氧氯普胺的新杂质作了进一步的结构确证，也开发了合适的检测方法并制定杂质限度，以便实现对药物更严格的质量控制。
发明内容
本发明要解决的技术问题是：提供一种甲氧氯普胺双氯新杂质，其结构如式Ⅰ所示：
发明人推测，上述杂质应当是在原料药合成路线中，通过氯代反应制备化合物SM1步骤中，发生了双氯代反应；后续又继续发生酯水解、缩合酰化反应得到；
本发明的第二方面提供了一种式I化合物在甲氧氯普胺或其盐的原料药、制剂有关物质检测时作为杂质对照品的用途。
本发明的第三方面提供了一种上述甲氧氯普胺双氯新杂质的检测方法，其色谱条件为：用辛烷基硅烷键合硅胶为填充剂；用磷酸盐缓冲液为流动相A，用乙腈为流动相B，优选用 0.050mol/L磷酸二氢钾溶液(加入0.2ml N,N-二甲基辛胺，用磷酸调节pH至4.0)为流动相 A；梯度洗脱；流速1ml/min；检测波长275nm；柱温为35℃。
进一步的，所述梯度洗脱程序如下：
| 时间(min) | 流动相A(％) | 流动相B(％) |
| 0 | 92 | 8 |
| 10 | 92 | 8 |
| 15 | 90 | 10 |
| 40 | 70 | 30 |
| 45 | 70 | 30 |
| 46 | 92 | 8 |
| 55 | 92 | 8 |
本发明中化合物的中文命名与结构式有冲突的，以结构式为准；结构式有明显错误的除外。
本发明首次公开了一种甲氧氯普胺双氯新杂质，制备得到的新杂质纯度大于99％，可作为甲氧氯普胺有关物质检测时的杂质对照品，有效监控甲氧氯普胺中的杂质含量，从而保证了甲氧氯普胺的安全性和有效性；
另外，常规HPLC检测方法不利于区分该杂质和甲氧氯普胺，从而易忽视该新杂质，因此即使甲氧氯普胺中的未知杂质均降至0.1％以下，也不能说明合成甲氧氯普胺的过程中未生成该杂质，更不可认为甲氧氯普胺与该杂质已完全分离，因此本发明开发的检测方法对于甲氧氯普胺双氯新杂质的检测具有明显优势。
附图：
图1：甲氧氯普胺双氯新杂质式I化合物的质谱图；
图2：甲氧氯普胺双氯新杂质式I化合物的氢谱图。
具体实施方式
以下结合实例说明本发明，但不限制本发明。在本领域内，技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
实施例1：
(1)4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)
向三颈瓶中加入式II化合物(36g,0.14mol)，DMF100mL，NCS(37.4g,0.28mol)加热至内温85℃，保温反应5小时，后处理将反应液倒入冰水中，用EA萃取100mL×3次，合并有机相用水洗100mL×2次，分液，无水硫酸钠干燥，浓缩得黄色固体30.2g，用THF/PE 5:16 重结晶，得23.6g类白色固体，收率57.9％，mp：137-139℃，ESI-MS(m/z):291.98[M+H]+。
(2)2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)
向250ml四颈瓶中加入4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)(20.0g， 0.069mol)，乙醇20mL，水100ml，氢氧化钠(8.7g，0.22mol)，升温至回流，反应3小时。停止加热，反应液转移至500ml瓶中，搅拌下开始滴加1M盐酸，调节pH至5左右，降温至12℃以下搅拌30min，抽滤，滤饼重新加100ml水，20℃以下打浆30min，抽滤，用20mL 水洗涤容器和滤饼，80℃烘干得15g粗品，粗品收率92.9％。
上述固体加242mL无水乙醇和45mL水加热直至溶清，关闭加热缓慢降温析晶，降温至 20℃以下搅拌3小时，抽滤，滤饼用20mL85％乙醇洗涤，80℃烘干得白色晶体12g，收率74.3％，HPLC纯度为99.8％。m.p.255℃分解，ESI-MS(m/z):258.01[M+Na]+。
(3)N-(2-二乙氨基乙基)-2-甲氧基-3,5-二氯-4-氨基苯甲酰胺(式I)
向250mL三颈瓶中加入2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)(9.6g,40.85mmol)，CDI (7.23g，44.63mmol)，DCM 100mL，加热至内温35℃，保温反应1.5小时，加入N,N-二乙基乙二胺(5.18g，44.63mmol)，回流1.5小时。后处理向瓶内补加100mL DCM稀释反应液，另加水20mL×3洗涤有机相，分液，无水硫酸钠干燥，浓缩得淡黄色油状物10.1g，收率 74.5％，HPLC纯度为99.8％。ESI-MS(m/z):334.13[M+H]+。
1H-NMR(CDCl3,400MHz)δ:8.148(s,1H),8.006(s,1H),4.781(s,2H),3.862(s,3H),3.470～3.518( m,2H),2.543～2.643(m,6H),1.006～1.042(t,6H)。
实施例2：
(1)4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)
向三颈瓶中加入式II化合物(36g,0.14mol)，DMF100mL，t-BuOCl(30.4g,0.28mol)加热至内温85℃，保温反应5小时，后处理将反应液倒入冰水中，用EA萃取100mL×3次，合并有机相用水洗100mL×2次，分液，无水硫酸钠干燥，浓缩得黄色固体30.2g，用THF/PE 5:16重结晶，得20.1g类白色固体，收率49.3％，mp：137-139℃，ESI-MS(m/z):291.98[M+H]+。
(2)2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)
向250ml四颈瓶中加入4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)(20.0g，0.069mol)，乙醇20mL，水100ml，氢氧化钠(8.7g，0.22mol)，升温至回流，反应3小时。停止加热，反应液转移至500ml瓶中，搅拌下开始滴加1M盐酸，调节pH至4左右，降温至12℃以下搅拌30min，抽滤，滤饼重新加100ml水，20℃以下打浆30min，抽滤，用20mL 水洗涤容器和滤饼，80℃烘干得14g粗品，粗品收率86.7％。
上述固体加242mL无水乙醇和45mL水加热直至溶清，关闭加热缓慢降温析晶，降温至 20℃以下搅拌3小时，抽滤，滤饼用20mL 85％乙醇洗涤，80℃烘干得白色晶体11g，收率68.1％， HPLC纯度为99.6％。m.p.255℃分解，ESI-MS(m/z):258.01[M+Na]+。
(3)N-(2-二乙氨基乙基)-2-甲氧基-3,5-二氯-4-氨基苯甲酰胺(式I)
向250mL三颈瓶中加入2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)(9.6g,40.85mmol)，CDI (7.23g，44.63mmol)，DCM 100mL，加热至内温35℃，保温反应1.5小时，加入N,N-二乙基乙二胺(5.18g，44.63mmol)，回流1.5小时。后处理向瓶内补加100mL DCM稀释反应液，另加水20mL×3洗涤有机相，分液，无水硫酸钠干燥，浓缩得淡黄色油状物10g，收率73.7％，HPLC纯度为99.5％。ESI-MS(m/z):334.13[M+H]+。核磁数据见实施例1。
实施例3：
(1)4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)
向三颈瓶中加入式II化合物(36g,0.14mol)，DMF100mL，NCS(37.4g,0.28mol)加热至内温85℃，保温反应5小时，后处理将反应液倒入冰水中，用EA萃取100mL×3次，合并有机相用水洗100mL×2次，分液，无水硫酸钠干燥，浓缩得黄色固体30.2g，用THF/PE 5:20 重结晶，得21.3g类白色固体，收率52.3％，mp：137-139℃，ESI-MS(m/z):291.98[M+H]+。
(2)2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)
向250ml四颈瓶中加入4-(乙酰氨基)-3,5-二氯-2-甲氧基苯甲酸甲酯(式III)(20.0g， 0.069mol)，乙醇20mL，水100ml，氢氧化钠(8.7g，0.22mol)，升温至回流，反应3小时。停止加热，反应液转移至500ml瓶中，搅拌下开始滴加1M盐酸，调节pH至5左右，降温至12℃以下搅拌30min，抽滤，滤饼重新加100ml水，20℃以下打浆30min，抽滤，用20mL 水洗涤容器和滤饼，80℃烘干得15.1g粗品，粗品收率93.5％。
上述固体加242mL无水乙醇和45mL水加热直至溶清，关闭加热缓慢降温析晶，降温至 20℃以下搅拌3小时，抽滤，滤饼用20mL 85％乙醇洗涤，80℃烘干得白色晶体12g，收率74.3％，HPLC纯度为99.8％。m.p.255℃分解，ESI-MS(m/z):258.01[M+Na]+。
(3)N-(2-二乙氨基乙基)-2-甲氧基-3,5-二氯-4-氨基苯甲酰胺(式I)
向250mL三颈瓶中加入2-甲氧基-3,5-二氯-4-氨基苯甲酸(式IV)(9.6g,40.85mmol)，TsCl (8.51g，44.63mmol)，DCM 100mL，加热至内温35℃，保温反应1.5小时，加入N,N-二乙基乙二胺(5.18g，44.63mmol)，回流1.5小时。后处理向瓶内补加100mL DCM稀释反应液，另加水20mL×3洗涤有机相，分液，无水硫酸钠干燥，浓缩得淡黄色油状物8g，收率59％， HPLC纯度为99.0％。ESI-MS(m/z):334.13[M+H]+。核磁数据见实施例1。
实施例4：甲氧氯普胺双氯新杂质的检测方法
供试品溶液取甲氧氯普胺原料药约10mg，精密称定，置10ml量瓶中，加甲醇：水(1:2) 10ml使溶解并稀释至刻度，摇匀，作为供试品溶液。
对照溶液精密量取供试品溶液，用流动相定量稀释制成每1ml中约含1μg的溶液，作为对照溶液。
色谱条件色谱柱为Welch Xtimate-C8(5μm,4.6×250mm)；以0.050mol/L磷酸二氢钾溶液 (加入0.2ml N,N-二甲基辛胺，用磷酸调节pH至4.0)为流动相A,乙腈为流动相B；流速1ml/min；检测波长275nm；柱温为35℃，按表1进行线性梯度洗脱。
系统适用性要求理论塔板数按甲氧氯普胺峰计算不得少于4000。
测定法精密量取供试品溶液与对照溶液，分别注入液相色谱仪，记录色谱图至主成分色谱峰保留时间的2倍。
表1有关物质的梯度洗脱程序
| 时间(min) | A(％) | B(％) |
| 0 | 92 | 8 |
| 10 | 92 | 8 |
| 15 | 90 | 10 |
| 40 | 70 | 30 |
| 45 | 70 | 30 |
| 46 | 92 | 8 |
| 55 | 92 | 8 |
表2甲氧氯普胺双氯新杂质的相对保留时间及限度
在上述色谱条件下，甲氧氯普胺双氯新杂质所示的相对保留时间为1.1，能与甲氧氯普胺原料药实现有效分离。该杂质分析方法的建立，为监控甲氧氯普胺的有关物质含量提供了一种行之有效的手段，更加有利于保障甲氧氯普胺的产品质量以及患者的用药安全。
试验例：
以TA97、TA98、TA100和TA102为测试菌株，以甲氧氯普胺双氯新杂质为样品进行平板掺入试验，结果表明致突比MR值为2.1，且有剂量-反应关系，可判定该杂质致突变阳性。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (3)
1.式I一种甲氧氯普胺双氯新杂质化合物在甲氧氯普胺或其盐的原料药、制剂有关物质检测时作为杂质对照品的用途，其结构如式Ⅰ所示：
所述甲氧氯普胺原料药合成路线如下：
2.一种根据权利要求1所述的甲氧氯普胺双氯新杂质的检测方法，其色谱条件为：用辛烷基硅烷键合硅胶为填充剂；用磷酸盐缓冲液为流动相A，用乙腈为流动相B；梯度洗脱；流速1ml/min；检测波长275nm；柱温为35℃。
3.根据权利要求2所述的甲氧氯普胺双氯新杂质的检测方法，其特征在于，所述梯度洗脱的程序如下：
。
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| CN105486776A (zh) * | 2016-01-14 | 2016-04-13 | 吉林师范大学 | 甲氧氯普胺的气相色谱分析方法 |
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